Current status and future perspectives of liquid biopsy in non-small cell lung cancer

Abstract

Molecular analysis is traditionally performed on tumor tissue. Although the number of mandatory tests for treatment decisions increases in patients with advanced non-small cell lung cancer (NSCLC), it is difficult to secure adequate tumor tissue for this purpose [1]. Small biopsy specimens, cell blocks, or aspirates are often the only available samples in patients with advanced NSCLC [2,3]. It is difficult to repeat tissue biopsies because they are invasive. Liquid biopsy could be an alternative or a complementary minimally invasive method for detecting molecular changes in NSCLC [1,2,4,5]. The clinical use of liquid biopsy to select patients with advanced NSCLC who are candidates for third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has been demonstrated in many clinical trials [6-10]. The United States Food and Drug Administration (FDA) approved Cobas EGFR Mutation Test v2 (Roche, Indianapolis, IN, USA) in 2018 as a companion diagnostic for third-generation EGFR TKI based on these results [11]. The Korea National Health Insurance Service (NHIS) has covered circulating cell-free tumor DNA (ctDNA) tests for EGFR mutations in advanced NSCLC since 2018. In this review, we present the current status and future perspectives of liquid biopsy in patients with NSCLC. BIOLOGY OF CIRCULATING TUMOR DNA Liquid biopsy refers to the collection and analysis of analytes from various body fluids such as blood, urine, sputum, and pleural fluid [12-14]. Different analytes can be present in a liquid biopsy including circulating tumor cells (CTCs), circulating cell-free DNAs (cfDNAs), circulating tumor RNAs (ctRNAs), circulating exosomes, tumor-educated platelets, proteins, and metabolites [15,16]. CTCs are intact, viable tumor cells circulating in the blood [12]. Cancer releases single or clusters of CTCs into the bloodstream during the course of hematogenous spread. cfDNA refers to all circulating DNA in body fluids. cfDNA can be derived from neoplastic as well as non-neoplastic cells [15,16]. cfDNA can be detected in other body fluids, including urine, saliva, or cerebrospinal fluid. ctDNA refers to a subgroup

The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer

“…However, as for the second and third cases, liquid biopsy missed SCLC transformation and, therefore, tissue biopsy is crucial when the liquid biopsy is not informative or histologic transformation is suspected based on clinical or radiological discordance, in line with previously reported cases [ 89 , 90 , 91 ]. Interestingly, Minari et al reported that a detected low ratio p. T790M/ EGFR activating mutation in liquid biopsy correlated with the presence of histological transformation to SCLC [ 91 ], which might be useful whenever a tissue biopsy is not feasible.…”

Future Perspectives in Detecting EGFR and ALK Gene Alterations in Liquid Biopsies of Patients with NSCLC

“…Currently, alterations in EGFR and ALK genes are considered important predictive biomarkers in NSCLC [ 5 , 6 ], since their identification in the tumor genome can determine a better outcome if a targeted therapy is implemented [ 14 ].…”

“…The EGFR mutation analysis in NSCLC patients’ liquid biopsies (namely, ctDNA) revealed to be highly correlated with treatment response when using the third-generation EGFR TKIs in several clinical trials [ 5 , 61 , 62 , 63 ]. Furthermore, EGFR mutation p.T790M was detected in ctDNA samples before the first signs of resistance to treatment occurred, allowing an early change of therapy [ 61 ].…”

“…The mutation(s)/alteration(s) in specific genes, such as EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) (among others), in NSCLC are considered predictive biomarkers since they can be used as targets for specific tyrosine kinase inhibitor (TKI) therapy, being also indicative of sensitivity or resistance to specific TKI treatments [ 5 , 6 ]. Although these biomarkers are scrutinized in the initial diagnosis (usually by PCR and Sanger sequencing methods) to define the therapy according to the molecular profile, a high number of patients acquire resistance during treatment.…”

“…Nevertheless, in order to apply this approach for routine clinical use, the validity of liquid biopsies’ analysis as being representative of the tumor itself needs to be further proved. Moreover, the scientific community needs to define evaluation criteria and to standardize the analytical methods [ 4 , 5 ].…”